Lower alkyl and alkenyl n-(1-naphthyl methyl) n-hydroxyethyl amines



' LOWER 'ALKYL ANDALKENYL N-(I-NAPH-Y.

THYL METHYL) N-HYDROXYETHYL M N r Y o .George Rieveschl, 'J'r., Grosse Pointe'Woods, and i William R. Coleman, Grosse Pointe, Mich., as-

signors to Parke, Davis & Company, Detroit,

Mich., a corporation of Michigan This inventionrelates' to a s new class of tertiary amines and to methods for obtaining the same. More specificaly, the invention relates to substitued p-hydroxy alkyl naphthylmethyl amines 7 Claims 260570.9)

I NoDrawing. IAp'plicatio'n December 2, 1945,; V :Serial No. 713,462 Y' der conditions similar to thoseset forth above. Another excellent method whichtmay be employed in the preparation bf these'zvaluable new products consists in reacting ethylene oxide or and their acid addition'salts The free bases of E l,2 -propylene oxide with an al kyl or alkenyl 1- the compounds of the present invention have the naphthyhnethy-l-*-amine*in l-anorganic formula, such as 'mthanoli ethanolp benzene,

R t Xylene, dioxane and the llkewhic h contains a s trace orasmall amount of water; m 10 These various processes may be diagram 1 cally illustrated as follows: 1 crux V a where R is"a lower-alkylor lower alkenylradical 15 FT TQ antiRJ is'hydrogenormthylw I In accordance witl the invention the new ter- (2) tiary ainines may be obtainedas the free base havingthe formula-given above or as an acid additio'n' salt of the base' with an" inorganic or 'organio' acid. T some ex m ms of}; the salts which may be prepared by the methods-hereinafter describedare the hydrochloride: hydrobromide', hydroiodide, sulfate, Sultanate; phosphate, acetate, citrate, oxalate, succinate, "benzene," tartra'te; phthalate, maleate, oleatelandth'likef' It has been found that" the compoundso f the present invention may be obtained by' several differentmethods. For" example, they may he preparedby the reaction oi a 'l-lialoinethylnaph-' thalne' with an alkyl' or alkenylpf-hydroxyalkyl aminepreierably in an inert organic solvent such as benzene, toluene or xyleneL A modification of this process involves'the use of an alkaline material to-react with the' 'minral acid formed during the reaction. When-the -reaction-is carried out in the presence of such materials a smaller quantity, of, amine is requiredsince ,;the amine is not removed from the action bygsalt"formation; 'In general, when no acidbiiidihgagent is employed it is preferable' to'use'about two or more equivalents of amine -foneach equivalent of l-halomethylnaphthalene. Some of the alkaline substances which may be used the process are alkali metal hydroxides, oxides; alcoholates, carbonates, bicarbonates, acetates and the like.

The alkaline earth metal hydroxides, oxides and qan nat slas w as tert ar io a ictbases:such aa-i y dinaxquino n and; th like mayalsor be s d-ti. F 1 ,3 .1: I Alternatively, an alkyl ,=or alkenyl l-naphthylmethyl amine canbe reacted/with a fl-hydroxy+ alkylqhalide under, substantially thesame conditionsras described-abovelforithelreaction of a 1- naphthylmethyl halide T with, an alkyl or alkenyl grhydroxyalkyl amine; Still another 3 method .for obtaining these new tertiary amino alcohols consists in alkylating;aipehydroxyalkyl l-naphthylmethyl amine witnlan.alkylrlonalkenylhalide un:

where R d have thesam s t je s e above'andXis chlorine'or brominei n h S b it t fieh al l oz a th z methyl amines and their acid addition salts are useful in the preparation of other organic compounds and find particular use in the preparation of sympatholytic' anifantihisiiamine agents.

The invention is illustrated by t-the following examples. 2 Example 1 .-Methyl B-hydrozvyethyi 1 -naphthylet yl min joHi OH21 I-CHiCH2OH' in, 100. .cc. pLbenemne; is dded eni h t rrlnalto a mixtr iienistiiig'" or 371 g? 5% iy m'ethyi ethanol'am'ine and 69 g. of anhydrous potassium carbonate in 100 cc. of benzene.

dition is complete the mixture is refluxed fored with ethen The ethefeirti iactsiaredried over "potassium carbonate, the 'drying agent removed After the ad M by filtration and the ether evaporated. The

" residue is distilled under reduced pressure to og- Example 2.Ethyl ,B-hydroxyethyl l ndpbtby lmethyl amine CHzCHa H cm-Ni-omcmon Ma) 88.3 :g.-.of 1 chloromethylnaphthalene dissol eqss :90 o enze -i adde dr wi e Wimi1 i 3fi 9 a so ti n 9 -;Q Meth 'ethanolamine in-100 of benzene. After. the eq itiq eee a e ng mi et e. ma ure is refluxed for four and one-halthours,cooledand the solid hydrochloride of -N-eth'yl ethanol amine removed by filtration. The benzene is'd-istilled from the filtrate and the residue distilledunder reduced pressure to obt ain the desirediethyl pa hydroxyethyl l-naphthylmethyl amine'boiling at 187 C. at 5 mm. V

The hydrochloride; salt of ethyl p-hydroxyethyl l-naphthylmethyl amine is prepared by dissolving a small amount of the product in' 'dry ether and adding an excess of dry hydrogen chloride gas or isopropanolic HCl. It separates from the solution as a white flufiysolid'whichmay be collected and purified [by recrystallization from isopropanol-ether mixture.

(b) 92.5 g. of ethyl l-naphthylmethyl amine is dissolvedin ,300 cc. of 95% alcohol and-gaseous ethylene oxidejbubbled into the solution until the weight gain o'f the reaction mixture is afiphroxi 'mately 25 g. The mixture-issallowed to stand twenty-four ihours, the alcohol distilled on using a water pump -"and"the residue distilled in high vacuo to obtain the-free base of ethyl c-hydroxyethyl l-naphthylmethyl amine as a colorless viscous oil; B. P. about 18'7 C. at 5 mm; Q

The hydrochloride saltwas prepared frointhis product and found to meltat thesame temperature as that prepared from the product produced by the method (a) described above. Mixing the hydrochloride salts produced .by; -methods .(a) and '(b) did not depress the.melting-points. Etamzile 55- 11 Prom/l p-hydroxyethyl. 1-naphp "'mzlhn'ethy'l'f'amine i I 'Ii IN'PCH1QH2O H 'extracts are madealkalinewithsodiumhydroxide sdlut'ion and the ''amine which separates extracttain the desiredln-propyl B-hydroxyethyl lnaphthylmethyl amine as a colorless oil.

The free base ma be converted to an acid additio'nz salt such as the hydrobromide by dissolving it in dry' ether and adding an excess of an absolute alcohol 'f'solution of hydrogen bromide.

The-"hydrobromide salt which separates from the .-;-solution; lS-CO110td and purified by recrystalliz'ati'on from isopropanolethyl acetate mixture.

V Example 4.Iso-propyl..p-hydroa:yethyl l-naphthylmethylamine Z, V V p (a) 58.9 g. of l-chloromethylr raphthalene in 50 cc. of xylene is added dropwise to a stirred and refluxing mixture consisting 20f ,35.1 g. of N-isopropyl ethanol amine and 50 g. of anhydrous potassium carbonate in 10Q;.%.cc.;'of Xylene. After the addition has been completedthe mixturegis refluxed overnight- (about; 16 hours). cooled {and poured into about loflccxof cold Water. The-organic': layer is separated, washed-with water and then extracted with :an excess eof dilute hydro- ,chloricracid: The acidic-extracts are made-ale ka'linev withv l0 N sodium [hydroxide solution and the free base extracted with ether- The ether extracts are ;dried, the-ether evaporated and the residue distilled under; reduced pressure to obtain the desired iso propyl ghydroxyethylfl-naphthylmethyl amine boilingat 1394-l C. at less than-1mm. I y

-'(b -99 y g. of -iso-propyl 'l-naphthylmethyl amine is dissolved pinabout 530.0.qcc. of: stockcben-q zene and ethylene :oxide bubbledinto the solution-until the weight gain o l-the reaction-mixture is approximately 25 g. The-benzene is removed bydistillationand the residue distilledin vacuo to obtain the free base of iso-propyl fi-hydroxyethyl. I-naphthylmethyl amine boiling-at approx-imately-'140 C. at 0.8 mm.

' (a) Gaseous "ethyleneoxidebubbled into a solution of '49 'gl' of'allyl -1-'naphthylmethyl amine in 150 cc. of methanol until the weight gain of the reaction isabout 12 g. 'The mixture is allowed to stand for one 'day and then the methanol removed by distillation. The residue is distilled'under 're'duced pressure to obtain the free base of allyl B hydro'xyeth'yl l naphthyl methyl amine as a colorless oil; B. -P. about M L-46 C. at 0.2mm V (b) '33.? g. of N'-allylfethanol-'amine is ;dissolved in 100 ce. of ury xyrene. "'50 "of anhydrous potassium carbonatfisadded and'the'inixture heated to reflux. 58;9"g. of l-chloromethyl naphthalene is added slowly to the stirred and refluxing mixture and after the addition is completed the reaction mixture is maintained at a temperature of 100 C. for about 20 hours. The mixture is cooled, poured into 400 cc. of cold water and the organic layer separated. After dilution with ether and washing, the organic layer is extracted with an excess of dilute hydrochloric acid, the' -acidic extracts'made alkaline with N scdi im hydroxide solutionand'the free base which separates extracted with; ether. The combined ether extracts are dried, the ether evaporated and the residue distilled in vacuo to obtain the desired 'allyl fi-hy'droxyethyl l-naphthylmethyl amine boiling at 144-146.5 C. at 0.2 mm; Thispmdu'ct isidentical with the product obtained by method ('gz) above.

' The-acid oxalate salt of this compound may be pre ared by dissolving 5 g.- of the productin cc'i 'of nitromethane and adding to this solution 15 cc. -ofa hot solution -'c ontaini1 ig one equivalent of o'xalic acid hydrate. By cooling theresultant solutionthe crystalline acid oxalate salt "of allyl p-hy'droxylethyl I-naphthyhne'thyl amine is ob-' tained. I r I Y Example 6.-n'-Butyl ,s-hydrorpyethyl l- -napltthyl methyl 'amin h I onlonzomom' CHrNrCHzCHzOH 88.3 g. of 1-chloromethylnaphthalene in 100 cc. of benzene is added dropwise to a stirred and refluxing mixture consisting of 58 5 g.-of -N-n-butyl ethanol amine and 69 g. of anhydrous potassium carbonate-in150 cc. of benzene. After the-additifon has-been completed,the mixture is refluxed for four hours, cooled and the salt removed by filtration. The benzene is distilledoff and the residue distilled in vacuo to obtain the desired nbutyl fl-hydroxyethyl' l-na'phthylmethyl amine;

BLP. 187'8 C.at 5 mm. w 'j This same compound can also'be prepared by bubbling gaseous ethylene oxide into a957,, al-' cohol or wet benzene solution containing 53lg. of n-butyl 1-naphthylmethyl amine until the weight-gain oi the reaction-mixture is about 12' g. After allowing the mixture-to-stand for awhile, the solvent is distilled off angilthe: residuflfiistilled under reduced pressure to obtain the tertiary amino alcohol.

The citrate salt of n-butyl ,B-hydroxyethyl 1- naphthylmethyl amine is obtained by treating a dry ether solution of'the base with an excess of citric acid dissolved in ether. The salt which separates from the solution as a finely divided pow-, der is collected and purified by washing with several portions of dry ether. 4 3 Example 7.Iso-butyl B-hydrqaiyetliyl I-naph- 1 58.9 "'g o'f -l-chloroniethylriapthalene in so cam xyleneis added dropwise to a stirred and refluxed mixture consisting of 39.1 g. of N-iso-but'yl ethanol amine, 30 cc. of pyridine and cc. of xylene."--After the addition has been completed, the mixture is' re'fiuxed for four hours, cooled and poured into 500 cc. 'of' cold water. The organic layer is diluted'with ether, removed and washed with "water.- "Ihis'layer is then extracted with-an excessfoi dilute hydrochloric acid, the acidic extracts made alk aline with 10 N sodium hydroxide solution and extracted with ether. The combined ether extracts'are dried, the ether evaporated and the re sidue "distilled in vacuo to obtain the de-' sired iso-butyl' p liydroxyethyl 1 -naphthylmethyl amine; B. P. 1-5'3 '==4 C. awe mm.

This 'samecompound maybe obtained by substituting an;.e quivalent amount (73.3 g.) of 1- bromomethylnapthalene for the l-chloromethylnaphthalene used in the above procedure.

. 5&9 g. of1echloromethylnaphthaleneidissolved inz501cc. of xylene is added slowly to a refluxing mixture composed of 39.1 g. of N-sec.-butyl ethanol amine. and 50 g. of potassium carbonate in.l00 cc. of xylene. 'After the addition has been completed, the mixture is. heated overnight, cooledand poured into 400 cc. of cold water. The organic layer isdiluted with ether, extracted with an excess of dilute hydrochloric acid and made alkaline with :10 N potassium hydroxide solution. The free-base which separates is extracted with ether, the-ether extracts dried and the ether distilled. The. residue is distilled under reduced pressureland'the fraction boiling at 1'73-80 C. at 2.5 mm, which consists of sec.-butyl 3-hydroxyethyl l-naphthylrnethyl amine, collected.

Example 9.n-Amyl fi-hydroxyethyl 1- naplithylmcthyl amine 7 omomon omom ?Hz-NCH2C H2(5H v" if' p'fin-amyl "l -naphthylmethyl amine is di'ssolvedin' cc.* 'of 95% lcohol and gaseous oxide bubbled into the solution until the ain m-weie 12 g? The mixture is allowed to stand overnight, the ameuqraisnuea and the residue distilled unlitiof the reaction mixture is about 1 refluxed :forsix hours,-cooled and treatedwith 500 cc. of water. 'The-organic layeris separated, extracted with an excess of dilute-hydrochloric acid and the aqueous extracts made alkaline with sodium hydroxide solution. (The hydrochloride of the-desired product is not very soluble in water and to avoid using large quantities of acid during the acid extraction of the'organic layer, the oily hydrochloride phase is added to the aqueous extracts before neutralization.) The free base of the amino alcohol which separates is extracted with ether, the ether extractsdried and the ether evaporated. The residue is distilled under reducedzpressure to obtain the n-amyl fi-hydroxyethyl l-.-naphthylmethyl amine as a colorless, viscous oil; 13. P. 163-6 C. at 0.7 m e V Ezrample 10.n-Hea;yl fi-hydroryethyl I-naphthylmethzll amine CHzOHzQHaCHzQHzCHr 58.9 g. of 1-chloromethylnaphthalene in 50 cc. of xylene is added dropwise/to a-*refluxing mixture consisting of 48.4 g. of N' n-liexyl ethanol amine, 50 g. of potassium carbonate and 100 cc. of xylene and the resulting mixture refluxed overnight. The cool mixture is poured into 500 cc. of waterand the organic layer separated after dilution with ether. treated with an excess of dilute hydrochloric acid, 'theaqueous extracts made alkaline with" '10 N sodiumhydroxide solution and the free base extracted with ether. (Since the hydrochloride salt of the desired product is quitev insoluble in water, it separates out as an oilduring the acid extraction. This oil layer is combined with the acidic aqueous extractsi) The e'therextracts are dried, the-ether'distilled and the residue distilled under reduced pressure to obtain the desired n-hexyl fl-hydroxyethyl l-naph'thylmethyl amine as av'iscous oil; 3. P. 163-70 C. at 0.55-mm.'-

(a) 58.9 g. of 1-chloromethylnaphthalene in 50 cc. of xylene is added dropwise to a refluxing solutionof- 34.4 g.- of N-ethyl iso-propanol amine and 30cc. of pyridine in 100 cc of xylene. -After the. addition has been completed, the solution is refluxed for four hours, cooled andpoured into 500 cc. of cold water. The organiclayer is die luted with ether, separated and extracted with an excess of dilute hydrochloric acid. The acidic aqueous extracts are made alkaline with N;sodium hydroxide solution, the free base extracted with ether and the ether extracts dried over potassium carbonate. The drying agent is -re-g moved by filtration, the ether evaporated and the residue distilled under reduced pressure to obtain the ethyl -,B-hydroxypropyl lenaphth-ylmethyl amine boilingat-138-40 C. at 0.6mm.

(b) A mixture consisting of -f7 g. oi d-hyidroxypropyl "l-naphthylmethyl: amine.-and,55;g,-

The organic layer is ex- 7 mixture-extracted, with ether.

of f-ethykbrpmide in 500 -'cc.-of benzene is refluxed for three hours andthen allowed to stand 'overjnight. 500 cc.' iof 5 N sodium hydroxidesolution is added and the organic layer separated. The organic layer is washed with water and extracted with an excess of dilute hydrochloric acid. The acidic aqueous extracts 'are made alkaline with sodium hydroxide solution, extracted with ether and the combined ether extracts dried over 1 0.- tassium carbonate. The drying agent is removed by filtration, the ether evaporated and the restdue-distilled under reduced pressure 5(about 1 mmgor less) in anefiicient distillation apparatus to --obtain the desired ethyl ,p-hydroxypropyl 1,-naphthylmethyl amine. Alternative1y,-the desired tertiary amine may be obtained from the residue remaining after evaporation of thezether'bytreatment of thepresidue with an excess of benzene sulfonylchlonide and aqueous alkali, The :insoluble benzene sulfonamide of the-starting material is filteredout astcompletel-y aspossible and washed with water andlthen asmall amount of dilute hydrochloric acid; ,-,The acidic; washings are made 1 alkaline and; combined with the main filtrate and the The ether extracts are dried and the ether evaporatedtorobtain substantially pure ethyl p-hydroxypropyl l-naphthylmethyl a r iner; 7

11 1. g... of -1rbromomethylnaphthalene in 100. 0g. of benzene is added dropwise with stirring'to ea refluxing-solution of. g.-of N-allyl iso-propa nol amine in 150 cc. of benzene, the resulting mixture refluxed for six hours, cooled and allowed to stand overnight. salt of N-allyl iso-propanol amine is removed .by washing the reaction mixture with 750 (BC-20f water and the benzene solution containing the free base 10f thedesired product driedoverpotassium carbonate; Thenbenzene is distilled oil and the residue distilled under reduced pressure (at about 1 mm. -or less) to obtain the allyl fl-hydroxyethyl l-naphthylmethyl amine asa colorless viscous oil.

I Eariltmiile' -Iso-propfll n-hydroxy'propyl I-naphthgjlmthylcmine V 7 CH5 I g cm o11zN-o'112 on an 30 g. of liquid 1,2-pro-pylene oxide is added to a solution of 99 g. of iso propyl l-naphthylmethyl amine in cc. of 95% alcohol and the resulting solution refluxed for'flfteen hours. The mixture is allowed to stand for twenty-fem" hours, the solvent removed by distillation/and the residue distilled under reduced pressure to obtain the free base of iso-propyl fi-hydrox propyl l-naphthylmethyl amine.

The hydrobromide V The l-halomethylnaphthalenes used as starting materials in the practice of the present invention may be prepared from naphthalene by processes well-known in the art, for example, by chloro or bromo methylation. The alkyl or alkenyl l-naphthylmethyl amines also used as starting materials may be obtained by treatment of a l-halomethylnaphthalene with an excess of an appropriate primary alkyl or alkenyl amine. For example, the iso-propyl l-naphthylmethyl amine which is used in Example 4b is prepared by refluxing a solution of l-chloromethylnaphthalene with about three to four equivalents isopropyl amine in absolute alcohol for a few hours. The alcohol is distilled off and the residue treated with water. Ether is added, the ether layer separated and extracted with several portions of dilute hydrochloric acid. The acidic aqueous extracts are made alkaline in the cold with sodium hydroxide solution and the free base extracted with ether. The ether extracts are dried, the ether evaporated and the residue distilled under reduced pressure to obtain the desired iso-propyl 1- naphthylmethyl amine.

What we claim as our invention is:

' l. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

R CHr-IQ-CHR-CHzOH where R is a lower alkyl radical.

3. A compound of the formula,

4. A compound of formula,

CH2 CH: CH:

Cm-aLomcmon 5. A compound of formula,

0&- CH: s

CHz-N-CHzCHzOH 6. A compound of the formula,

i CH:NCH2CH2OH 7. A compound of the formula,

CHaCHzCHzCHI CHr-N-CHICHIOH GEORGE RIEVESCHL, JR. WILLIAM R. COLEMAN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Wedeklnd: Ann.," 471, pp. 73-112 (1929). 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ADDITION SALTS, SAID FREE BASE HAVING THE FORMULA, 